Project Summary/Abstract Statins are the most widely used medication in reducing blood cholesterol and preventing coronary heart disease. However, adherence is poor; studies report fewer than half of patients take statins as prescribed. One of the main barriers in statin adherence is symptoms related to myopathy which include muscle discomfort, weakness, and rhabdomyolysis, a potentially life-threatening condition. Yet, the underlying mechanism of statin-induced myopathy (SIM) remains poorly understood due to 1) complex pleiotropic and myotoxic effects of statins, 2) limited accessibility of affected patients? myocytes, and 3) lack of appropriate animal models to investigate the differential susceptibilities of statin toxicity. Previous clinical and scientific findings suggest off-target effects of statins in the mitochondria as the mechanism of SIM, but the results have not been validated in human studies. Recent advances in the generation of skeletal muscle cells (SkMCs) from human iPSCs present an unprecedented opportunity to model skeletal muscle diseases such as SIM. Herein, I propose to investigate the disease mechanisms of SIM by using a patient-specific iPSC platform. Specifically, I will test the central hypothesis that SIM is mediated via skeletal muscle-specific off-target effects resulting in mitochondrial redox imbalance, metabolic compromise and subsequent cell death. For this study, I will first characterize metabolic consequences of statins in iPSC-derived SkMCs and patient myocytes (Aim 1). I will then investigate the mechanism behind patient-specific differential myopathic susceptibility to statins by comparing iPSC-SkMCs derived from patients tolerant of statins to patients suffering from SIM (Aim 2). Finally, I will identify novel genes critical in the pathogenesis of SIM utilizing a genome-scale CRISPR interference screening technique by specifically silencing genes involved in statin toxicity and thereby conferring statin tolerance (Aim 3). The findings from this study will elucidate the molecular mechanism of SIM and facilitate the creation of precision medicine tools to enhance the diagnosis, prevention and treatment of SIM.